Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-10-11
2003-01-14
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S373000, C514S415000, C514S323000, C548S511000, C546S201000
Reexamination Certificate
active
06506758
ABSTRACT:
This invention relates to certain novel compounds, to a process for preparing such compounds, to pharmaceutical compositions containing such compounds and to the use of such compounds and compositions in medicine.
Diseases associated with loss of bone mass are known to be caused by over activity of osteoclast cells. It is also known that certain compounds, usually related to bafilomycin, are useful for treating such diseases: For example International Patent Application, publication number WO 91/06296 discloses certain bafilomycin macrolides for the treatment of bone affecting diseases.
However, bafilomycin derivatives are not selective for osteoclasts in humans. The use of these compounds is therefore associated with unacceptable toxicity due to generalised blockade of other essential v-ATPases. Indeed, to date there is no known treatment which is selective for the human osteoclasts.
The search for a successful treatment for diseases associated with loss of bone mass in humans is further complicated in that the nature of the therapeutic target for the selective inhibition of the osteoclasts is controversial. Thus Baron et al. (International Patent Application publication number WO93/01280) indicate that a specific vacuolar ATPase (V-ATPase) has been identified in osteoclasts as a potential therapeutic target. However, the Baron work was carried out in chickens and Hall et al (
Bone and Mineral
27, 159-166, (1994)), in a study relating to mammals, conclude that in contrast to avian osteoclast V-ATPase, mammalian osteoclast V-ATPase is pharmacologically similar to the v-ATPase in other cells and, therefore, it is unlikely to be a good therapeutic target.
We have now found a group of compounds which are selective for mammalian osteoclasts, acting to selectively inhibit their bone resorbing activity. These compounds are therefore considered to be particularly useful for the treatment and/or prophylaxis of diseases associated with loss of bone mass, such as osteoporosis and related osteopenic diseases, Paget's disease, hyperparathyroidism and related diseases. These compounds are also considered to possess anti-tumour activity, antiviral activity (for example against Semliki Forest, Vesicular Stomatitis, Newcastle Disease, Influenza A and B, HIV viruses). antiulcer activity (for example the compounds may be useful for the treatment of chronic gastritis and peptic ulcer induced by
Helicobacter pylori
), immunosupressant activity, antilipidemic activity, antiatherosclerotic activity and to be useful for the treatment of AIDS and Alzheimer's disease. In a further aspect, these compounds are also considered useful in inhibiting angiogenesis, i.e. the formation of new blood vessels which is observed in various types of pathological conditions (angiogenic diseases) such as rheumatoid arthritis, diabetic retinopathy, psoriasis and solid tumours.
Accordingly, the invention provides a compound of formula (I):
or a salt thereof, or a solvate thereof, wherein:
A represents an optionally substituted aryl group or an optionally substituted heterocyclyl group;
R
a
represents —CO—NR
s
R
t
wherein R
s
and R
t
each independently represent hydrogen, alkyl, substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heterocyclyl or an optionally substituted heterocyclylalkyl group, or R
s
and R
t
together with the nitrogen to which they are attached form a heterocyclyl group;.
R
1
and R
2
each independently represents hydrogen, hydroxy, amino, alkoxy, optionally substituted aryloxy, optionally substituted benzyloxy, alkylamino, dialkylamino, halo, trifluoromethyl, trifluoromethoxy, nitro, alkyl, carboxy, carbalkoxy, carbamoyl, alkylcarbamoyl, or R
1
and R
2
together represent methylenedioxy, carbonyldioxy or carbonyldiamino; and
R
3
represents hydrogen, alkanoyl, alkyl, aminoalkyl, hydroxyalkyl, carboxyalkyl, carbalkoxyalkyl, carbamoyl or alkylsulphonyl and arylsulphonyl.
Examples of aryl groups represented by A include phenyl and naphthyl.
Examples of heterocyclyl groups represented by A include furyl groups.
Suitably, R
1
and R
2
each independently represents a halogen substituent, for example chloro.
Suitable positions for substitution for R
1
or R
2
are the 4, 5, 6 or 7 position. favourably the 5 or 6 position.
In a preferred aspect R
1
is chloro, especially 5-chloro. and R
2
is chloro, especially 6-chloro.
Suitably, R
3
represents hydrogen.
When R
s
or R
t
represent alkyl or substituted alkyl, suitable alkyl groups are C
1-6
alkyl groups, for example C
1
, C
2
, C
3
, C
4
and C
5
alkyl groups, favourably ethyl, propyl or butyl.
When R
s
or R
t
represent substituted alkyl, favoured groups are 2-(dialkylamino)ethyl, 3-(dialkylamino)propyl, 4-(dialkylamino)butyl, 3-[4-(3-chlorophenyl)piperazin-1-yl]propyl, 3-[4-(3-hydroxyphenyl)piperazin-1-yl]propyl, heterocyclylmethyl, heterocyclylethyl or heterocyclylpropyl groups.
Suitably, R
s
represents optionally substituted heterocyclyl, and aryl.
Suitably, R
s
represents optionally substituted heterocyclylalkyl.
Suitably, R
t
is hydrogen.
In a favoured aspect, R
s
represents an optionally substituted piperidinyl group, especially a 4-piperidinyl group.
Subsituents for the piperidinyl ring include alkyl, fused cycloalkyl and hydroxyalkyl, polyhydroxyalkyl.
Favoured substituents for piperidinyl groups are alkyl groups.
When the piperidinyl group is substituted it is preferred if the substituents are attached to one or both of the carbon atoms alpha to the nitrogen atom.
An example of a substituted piperidinyl groups is a 1,2,2,6,6-pentamethylpiperidin-4-yl group and 2,2,6,6-tetramethylpiperidin4-yl.
When R
s
represents heterocyclylalkyl, suitable heterocyclyl groups are optionally substituted saturated single ring heterocyclic group having 5 to 8, preferably 5 or 6, ring atoms, which atoms include 1, 2 or 3 heteroatoms selected from O, S, or N; for example an optionally substituted piperazinyl group; Suitable optional substituents for the heterocyclyl groups are optionally substituted aryl groups, for example hydroxyphenyl or chlorophenyl groups.
There is a moiety, referred to herein as moiety (b), which forms part of formula (I) and which has the formula shown below:
In one preferred aspect moiety (b) represents a moiety of formula (c):
wherein R
a
is as defined relation to formula (I) and R
4
represents hydrogen, hydroxy, alkoxy, alkythio, halogen or a group NR
u
R
v
wherein R
u
and R
v
each independently represent hydrogen, alkyl or alkylcarbonyl.
Suitably R
4
is located meta to R
a
.
Suitably, R
4
represents hydrogen or alkoxy, preferably alkoxy.
An example of R
4
is hydrogen. An example of R
4
is methoxy.
Particular examples of formula (I) are those of example numbers 2, 7 and 8.
As used herein, the term “alkyl” includes straight or branched chain alkyl groups having from 1 to 12 , suitably 1 to 6, preferably 1 to 4, carbon atoms, such as methyl, ethyl, n- and iso-propyl and n- iso-, tert-butyl and pentyl groups, and also includes such alkyl groups when forming part of other groups such as alkoxy or alkanoyl groups.
As used herein, the term “aryl” includes phenyl and naphthyl, especially phenyl.
Suitable optional substituents for any aryl group include up to 5 substituents, suitably up to 3 substituents, selected from alkyl, alkoxy, thioalkyl, hydroxy, halogen, trifluoromethyl, alkylcarbonyl, cyano, nitro, or a group-NR
u
R
v
wherein R
u
and R
v
each independently represent hydrogen, alkyl or alkylcarbonyl.
Suitable arylalkyl groups include aryl-C
1-3
-alkyl groups such as phenylethyl and benzyl groups, especially benzyl.
Preferably, substituted aralkyl groups are substituted in the aryl moiety.
As used herein, the term “heterocyclyl” includes saturated or unsaturated single or fused ring heterocyclic groups, each ring having 4 to 11 ring atoms, especially 5 to 8, preferably 5, 6 or 7 which ring atoms include 1, 2 or 3 heteroatoms selected from O, S, or N.
Suitable optional substituents for any hetero
Gagliardi Stefania
Nadler Guy Marguerite Marie Gerard
Novella Pietro A T
Kinzig Charles M.
Liu Hong
Madden Laura K.
McCarthy Mary E.
Shah Mukund J.
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